Since it was first identified as a member of the peroxisome proliferator-activated receptors (PPARs) in 1994, specific roles for the PPAR-beta (also referred to as PPAR-delta) have remained elusive, Recent data suggests that the PPAR-beta may be involved in epithelial cancer including skin and colon. PPAR-beta expression is upregulated in response to topical application of a tumor promoter (TPA), in human colon tumor cells with an inactivated APC gene, and in human and azoxymethane-induced rodent colon tumors providing the first evidence suggesting that this receptor contributes to the mechanisms of epithelial cancers. Increased expression of beta-catenin caused by a mutant APC gene mediates transcriptional upregulation of PPAR-beta in colon tumor cells, demonstrating that PPAR-beta activation is downstream of the initial molecular events in the etiology of colon cancer. The central hypothesis of this proposal is that one functional role for PPAR-beta is to modulate target gene expression that leads to colon carcinogenesis. The first specific aim is to develop two model systems to test the hypotheses that PPAR-beta is essential for colon carcinogenesis. The first model will utilize crossing the PPAR-beta-null mouse line with APC min+/- mice and the second model will assess azoxymethane-induced colon cancer in the PPAR-beta null mouse. Results from these experiments will determine if increased PPAR-beta expression is central to the mechanisms underlying colon cancer. Western-style diets with a high fat content have been linked to higher incidence of colon cancer in both human and animal models and dietary fatty acids are known ligands for PPAR-beta. The second specific aim will test the hypothesis that increased colon cancer resulting from a high fat diet is dependent on PPAR-beta. Treatment with non-steroidal anti-inflammatory drugs (NSAIDs) is used to prevent colon tumor formation, and may be due to inhibition of PPAR-beta-dependent target gene transcription and/or inhibition of COX metabolism. Preliminary data suggests that the beneficial effects of sulindac are mediated by the PPAR-beta. The third specific aim will determine if inhibition of colon carcinogenesis by the NSAID sulindac is mediated by PPAR-beta. Results from this work will also determine whether inhibition of PPAR-beta-dependent target gene transcription, inhibition of COX activity that may be influenced by PPAR-beta, or both, are critical to the mechanisms underlying sulindac inhibition of colon cancer. Combined, this work will clarify specific functional roles for the PPAR-beta in the molecular mechanisms underlying genetic, dietary and chemically induced colon cancer and in the prevention of this disease; thus providing future therapeutic targets to prevent colon cancer.